Study Confirms that Combination Treatment Using a Protease Inhibitor
Can Delay HIV Disease Progression and Death

Research supported by the National Institute of Allergy and Infectious Diseases (NIAID) has demonstrated that in patients with advanced HIV disease the combination of a protease inhibitor plus two nucleoside analogue reverse transcriptase inhibitors (RTIs) is significantly more effective in reducing the occurrence of AIDS-defining illnesses or death than two RTIs alone. The study, known as ACTG 320, was designed to determine the efficacy and safety of the protease inhibitor indinavir when given in combination with zidovudine (ZDV) [or stavudine (d4T)] and lamivudine (3TC), as compared to ZDV (or d4T) plus 3TC.

As a result of recent data showing the dramatic effectiveness of protease inhibitors in lowering viral burden, strategies using protease inhibitors in combination with other drugs are being widely used. "The results of ACTG 320 confirm the importance of including protease inhibitors in treatment strategies for patients with advanced HIV disease," says Anthony S. Fauci, M.D., NIAID director. "Significantly, the current study provides additional evidence that combination approaches using protease inhibitors can reduce the risk of death."

Preliminary results of the study were reviewed Feb. 18, 1997, by an independent data and safety monitoring board, which recommended early termination of enrollment and closure of the study. They based this recommendation on the significant benefit of the triple combination including indinavir in delaying disease progression and death.

"The further, significant reduction in disease progression conferred by indinavir when given as part of a three-drug combination illustrates the rapid progress that the field of HIV therapeutics has made in the last two years and suggests that further benefits can be achieved with regimens of ever-increasing potency," commented Scott Hammer, M.D., protocol chair of ACTG 320.

Volunteers in the study had CD4+ T cell counts below 200 per cubic millimeter (mm3) of blood at study entry and had taken ZDV for at least three months, but had received less than one week of 3TC and no protease inhibitors. The mean baseline CD4+ T cell count of the participants was 86 cells/mm3. They were randomized to receive either the combination of ZDV (600 mg/day), 3TC (300 mg/day) and indinavir (2400 mg/day), or ZDV plus 3TC plus placebo. Participants intolerant to ZDV could use stavudine (d4T), and those developing toxicities or experiencing mild disease progression were allowed to change to other approved nucleoside analogues. The majority of participants received ZDV and 3TC for the duration of the study.

A total of 1,156 HIV-infected volunteers participated in ACTG 320. Participants were enrolled at 33 sites of the NIAID-supported AIDS Clinical Trials Group, and at seven sites of the National Hemophilia Foundation. They were followed for a median of 38 weeks, with some patients being followed for up to one year. Further studies are needed to understand the long-term impact of this triple combination. Sub-studies of ACTG 320 are currently being analyzed, including a study of how the various treatments affect the amount of virus in patients' blood and to characterize the development of drug resistance in the different treatment arms.

Survival and a delay in disease progression were significantly better in patients receiving triple combination therapy. In that group, AIDS-defining illnesses, including opportunistic infections and cancers, and deaths were decreased by approximately half. Sixty-three instances of disease progression (including AIDS-defining illnesses and deaths) occurred in volunteers on the ZDV/3TC arm versus 33 in volunteers on the triple combination arm. The benefit was statistically significant for the subset of patients with CD4+ T cell counts less than 50/mm3 and there was a similar trend for patients with CD4 counts between 50 cells/mm3 and 200 cells/mm3. There were 18 deaths in the double therapy arm versus eight deaths in the triple therapy arm.

In addition, the safety of each treatment regimen was closely monitored. There were no major differences in the safety or toxicity of the two treatment regimens and the study medications were well-tolerated.

The drugs used in this study were provided by their manufacturers: Merck & Co., Inc. (indinavir/Crixivan®), Glaxo Wellcome, Inc. (ZDV/Retrovir® and 3TC/Epivir®), and Bristol-Myers Squibb Co. (d4T/Zerit® and ddI/Videx®). Merck also provided financial support for the study.

NIAID, a component of the National Institutes of Health (NIH), supports scientists and scientific studies at universities, medical schools and research institutions in the United States and abroad. As part of its efforts to improve the quality and duration of life of HIV-infected individuals, the Institute supports four diverse AIDS clinical trials programs: the Adult AIDS Clinical Trials Group, the Pediatric AIDS Clinical Trials Group (PACTG), the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), and the Division of Intramural Research clinical trials program on the NIH campus. NIH is an agency of the U.S. Department of Health and Human Services.

NIAID press releases, fact sheets and other materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov.